A gene is considered a candidate gene for type 2 diabetes in Pima Indians if 1) it has a known physiological function in a pathway relevant to type 2 diabetes/obesity or 2) it is associated with diabetes/obesity in another human population or in an animal model. In the past year we have directly sequenced and genotyped all detected variants in more than 20 physiologic candidate genes for associations with BMI or diabetes. We have recently found Sim1 to be the first major susceptibility gene for obesity in the Pima Indians, where variation in this gene accounts for approximately 16 lbs. We have also been collaborating with Dr Mark McCarthy and Dr Andrew Hattersley on the FTO gene, which has recently been reported to be highly associated with BMI in Caucasians. Our group has the first data on this gene in a non-Caucasian population, where the gene shows a similar association with BMI in Pima Indians, and has also furthered the initial finding by showing that this gene has a specific effect on determining fat cell size- an observation that is being followed up on in knockout mice. In contrast, we have shown that variation in TCF7L2, which strongly predicts type 2 diabetes in multiple ethnic groups, has no role in determining type 2 diabetes in Pima Indians.